Molecular Similarities Between Trypanosoma Cruzi Microtubule Associated Proteins, Mammalian Interferons, and TRIM Genes

doi:10.21203/rs.3.rs-3002014/v2

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Molecular Similarities Between Trypanosoma Cruzi Microtubule Associated Proteins, Mammalian Interferons, and TRIM Genes

https://doi.org/10.21203/rs.3.rs-3002014/v2

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This study identifies DNA sequence similarities between T. cruzi Genbank M21331, coding for Antigen 36, and genes in two families coding for innate immunity proteins: TRIM genes, and Interferon (INF) genes. From the bioinformatics analysis, TRIM37 and TRIM40 showed 18% and 9.7% identity, respectively, to M21331, and four other TRIM genes had identities greater than 5%. When human IFNα, IFN-β, and IFN-γ genes were compared to M12331, the percent identities were 13.6%, 12.6%, and 17.9%, respectively. To determine the minimum number of gene homologues of Antigen 36 (Ag36), a BLAST-p search was conducted with it versus the T. cruzi genome. The BLAST-p revealed that the Ag36 gene of T. cruzi had 14 homologous genes sequences (MAP genes with 100% amino acid sequence identity to M21331). To partially extend these findings to other non-human genes, a study of comparable TRIM21 region sequences among mammalian species showed that the relationship between the sequences were also present in canine, shrew, ferret, bat, feline, armadillo, and aardvark species. The function of this MAP gene family of T. cruzi genes having similarity to human innate immune genes is not known but may be related to the resistance of T. cruzi to the host innate immune system during its intracellular infection.

Biological sciences/Evolution

Biological sciences/Genetics

Biological sciences/Immunology

Biological sciences/Microbiology

Chronic Chagas Cardiomyopathy (CCC)

Interferon (INF)

Interleukin (IL)

Microtubule Associated Protein (MAP)

Needleman-Wunsch (NW) algorithm

Tripartite Motif (TRIM)

Trypanosoma cruzi (T. cruzi)

Chagas’ disease has become a progressive emerging disease in the United States. In South and Central America, the disease may affect over 18 million people. Typically, the causative agent, Trypanosoma cruzi, may not immediately kill the host, but the parasite keeps the host in check, in order to maximize transmission and therefore, prolong its life cycle. The mammalian host can gradually develop illness from an acute or mild form of the disease to a latent stage, to a chronic stage. There is significant mortality due to the Acute and Chronic stages of this disease. In particular, CCC is thought to be caused by an autoimmune attack upon nerve and/or heart tissue (1).

Recognition of this parasite as a potential threat to the US blood supply was in 1992 when several biopharmaceutical companies developed diagnostic tests to identify this disease (2). In 1995 the FDA accepted a 510(k) diagnostic test (Enzyme Immunoassay) for Chagas’ disease (3; 4). Progressive improvements to identify several highly antigenic T. cruzi molecules reactive with human chagasic antiserum were made in subsequent years (2006-2011); the Association for the Advancement of Blood and Biotherapies (AABB), the FDA, CDC, and WHO have now recognized this disease as one of the 13 donor screening assays for Infectious Agents.

Presently there are no vaccines against Chagas’ disease and therapeutic agents (benznidazole) have only recently (2017) been FDA approved for use in children ages 2 to 12 years old with Chagas’ disease. Side effects are common, frequent, and severe with increasing age. In this regard, alternative methods for treatment are necessary. Our primary focus has been to search and identify highly antigenic T. cruzi molecules reactive with human chagasic antiserum (3; 5). To this end, one cloned gene from T. cruzi amastigotes was chosen, sequenced and found to be identical to the repetitive antigen Clone 36, "Antigen 36"(6).

Search of GenBank using our DNA sequence translated by the TFASTA program revealed identity of Human Ro52 with the translated sequence in the second reading frame of Ag36. Direct comparison of the Ag36 DNA sequence with Ro52 DNA sequence revealed 70% identity in one sequence of 44 nucleotides between the Ag36 DNA sequence and TRIM21, the gene for human Ro52 (7). Here we query TRIM genes, and other innate mammalian immune genes, for any such extended sequence identities using established bioinformatic tools (8).

TRIM genes are a large family of mammalian and vertebrate genes, which share homologous domains(9; 10). Many of these genes code for E3 Ubiquitin ligases, and many of them function in regulating innate immunity and immunity to viruses and cancer (11; 12). For example, TRIM21 is an E3 Ubiquitin ligase that modifies transcription factors for IFN-α and IFN-β and other cytokines, thereby dampening (or stimulating) INF gene transcription (13; 14).Knock out of TRIM21 in mice strains showed that they were susceptible to tissue inflammation and systemic autoimmunity after injury induced by skin tagging (15). We proposed that the partial gene homology between TRIM21 and Ag36 may cause RNA interference, , or down-regulation of Ro52, leading to the autoimmunity of CCC (16; 17). We also proposed that for the parasite, the interference could be beneficial during its invasion of macrophages by blocking TRIM21 stimulation of innate immunity. It would be useful to explore any similarities between Ag 36 and the genes of other mammalian TRIM21 genes to validate the sequence similarity observed between human TRIM21 and the T. cruzi Ag36 gene. In this work, we extend the comparison of DNA sequences of Ag36 to eighteen additional mammalian TRIM21 sequences, using the Needleman-Wunsch (NW) algorithm to determine partial sequence similarities, and to determine if the similarities observed were a unique phenomenon in primates, or whether they extend to other mammals. .

In 2021, DeCuir and his team (18) published the complete sequence of the nuclear genome of T. cruzi (strain SC43). This sequence and others enabled (a) our description of T. cruzi genes homologous to Ag36; (b) our finding that there are human TRIM family genes similar to them; and (c) our discovery that T. cruzi Ag36 gene sequence is similar to human INF- α, β, and γ genes. Studies by Cunha-Neto et al (19) and Marin-Neto et al (20) suggest that IFN-γ mediated chronic myocardial inflammation may theoretically prolong an ongoing inflammatory process which could contribute to the pathogenesis of CCC (17; 21; 22).

A BLAST-p search of Ag36 (Genbank M21331) versus non-redundant T. cruzi Genbank genes was performed on-line at https://ncbi.nlm.nih.gov and the result files were directly down-loaded. The BLAST-p searched “all non-redundant GenBank Coding Sequence (CDS)” of T. cruzi.

Mammalian TRIM sequences, human INF, and (Interleukin) IL-1 and IL-2 sequences were retrieved from Genbank or the University of California Santa Barbara databases, and the sequences compared to the Ag 36 gene (Genbank M21331) with tools at https://usegalaxy.org (23; 24). To determine gene sequence similarity, gene sequences were aligned by the NW algorithm(25). The NW global alignment tool is an algorithm used to find the optimum alignment (including gaps) of two sequences when considering their entire length. A higher score indicates that fewer gaps were inserted to achieve the alignment. The dataset and workflows are stored at a persistent dataset web link (Data Availability Statement below).

Sequences of TRIM21 genes from 19 mammalian species, other than human, were also retrieved from Genbank or the University of California Santa Barbara databases, and sequences compared to the Ag36 gene (Genbank M21331) with tools at https://usegalaxy.org. The dataset and workflows are stored at a persistent web link (Data Availability Statement). The mammalian TRIM21 genes analyzed represented the following: primates (human, chimpanzee), in addition to mouse, rat, gerbil, dog, cat, nine-banded armadillo, shrew, lynx, ferret, marmoset, bat, sheep, cow, deer, horse, aardvark, rabbit, and goat. Gene sequences were aligned by the NW algorithm.

A BLAST-p search of the https://ncbi.nlm.nih.gov database with the Ag 36 sequence, with one mismatch, revealed fourteen T. cruzi Genbank entries (“100% positive” in Table 1). Since these genes code for proteins referred to in Genbank listings as “Microtubule Associated Protein” (MAP), or “Putative Microtubule Associated Protein,” or “Hypothetical Microtubule Protein,” we will refer to these as MAP genes. Thirty-seven of the BLAST-p results have sequences greater than 94%, which are identical to Ag36 with e values <10^-15. These were within the proteins found in four entries, Genbank Accession numbers KAF8288323.1; PWU83737.1; PWU83737.1; and RNC30406.1 (data not shown).

Since TRIM genes share DNA sequence identities between their conserved domains(10), and TRIM21 had shown sequence similarity to Ag36 in previous studies (7), we chose to test the sequences of 47 human TRIM genes (listed in Table 2) for similarity to the Genbank M21331. Table 2 demonstrates that TRIM37 had an 18% identity in sequence to Genbank M21331 and TRIM40 had a 9% identity. Thirteen of the human TRIM genes showed 4.0 to 6.4% sequence identity. Twenty-eight TRIM genes had less than 4.0% identity. While the overall similarities were less than 18%, we note that there are stretches of much greater similarity, such as 68% (41/60) of nucleotides 836-916 of Human TRIM21 compared with Ag36. Since TRIM proteins are intrinsic to innate immunity, we examined GenBank M21331 for similarity to several key cytokines involved in innate immunity, for example, INFs and ILs. Table 3 displays the results for human IFN-α, IFN-β, and IFN-γ, as well as human IL-1 alpha and human IL-2. Human IFN-γ showed 17.9% identity; though its NW significance score (82.5), was less than the other INFs examined. Human IFN-α showed 13.6% identity with a higher NW score (134.0). Inspection of the NW alignment (Figure 1) showed a stretch of twenty M21331 nucleotides aligned with IFN-α nucleotides 368-388, with six gaps inserted to make the match. Note that there is a “hot spot” of 68% similarity (23/34) in nucleotides 361-395 of human INF-α compared with Ag36.

Comparison of TRIM21 (nucleotides 856-916) to Ag 36 in Mammals

To further verify the similarities found between human immune genes and T. cruzi MAP genes, we compared GenBank M21331 wit, numerous other mammalian TRIM21 genes. Therefore, an assessment to associate these mammalian TRIM21 genes to the T. cruzi Ag 36 DNA sequence was accomplished using the NW algorithm in the https://usegalaxy.org (23) bioinformatics tool base. In the TRIM21 nucleotide stretch 856-916, the greatest percentage homology was human (68%), followed by chimpanzee (60%), dog (57%), and shrew (50%) (Table 4). Seven other species showed partial homologies in the compared region of 32% to 45%. The nine other mammalian TRIM21 genes shown in Table 4 had no significant similarity (<2%) in this region. Of those mammalian TRIM21 showing similarity, the percentages of identity correlate with the phylogeny of these mammals.

It is striking that T. cruzi contains 12 genes that are 100% identical in the 37 of 38 positions, to Ag36 sequence. It is also remarkable, considering the many hundreds of millions of years when the protozoan ancestor of T. cruzi separated from that of mammals, that these T. cruzi MAP genes show sequence similarities with human TRIM genes, and IFN-α, IFN-β, and IFN-γ genes. The gene identities observed between the MAP proteins and human INFs have possible implications during T. cruzi intracellular infection. We speculate that the T. cruzi mRNAs for the 51 MAP-like proteins (14 homologues plus 37 with 94% identity), could down regulate expression of IFN-α or IFN-γ by RNA interference IFN-α IFN-β, or , for example, if the parasite mRNAs found their way into the host cellular cytoplasm. As evidence that this may occur, Bayer-Santos et al (26) report that extracellular vesicles secreted from metacyclic T. cruzi trypomastigotes contain parasite mRNAs, in addition to other varieties of small and larger RNA. RNA interference by the MAP RNA could also affect the levels of TRIM proteins such as human TRIM37, TRIM40, or TRIM21 that were found to have sequence similarities to the MAP genes. It is intriguing that the TRIM gene with the most sequence identity to GenBank M21331, TRIM37, causes severe cardiomyopathy, among other birth defects, when mutated in humans (27). Loss of the TRIM37 due to RNA interference could result in loss of function in a fashion similar to that observed with the TRIM37 mutations reported to inactivate that protein. Conversely, parasite MAP mRNAs could block expression of TRIM21, leading to a dampening of these key regulators of INF and causing autoimmunity, such as seen in CCC (16).

In addition, the gene similarities of Ag36 to human TRIM21 were verified by comparing the T. cruzi Ag36 gene sequence with various mammalian TRIM21 gene sequences (TRIM21 being the most sequenced mammalian TRIM gene). These results correlated with the mammalian phylogeny. Primate TRIM21 were most similar to Ag36, followed by dog, shrew, ferret, bat and cat. More distant mammals to humans, such as sheep, rats and mice, were not similar. Of these species, humans and dogs have been shown to have CCC after T. cruzi infection (28; 29; 30).

The Ag36 gene of T. cruzi, Genbank M21331, was found to have 14 homologous and 37 highly similar genes in the T. cruzi genome. Comparison of this sequence to human TRIM genes showed that TRIM37 and TRIM40 had 18% and 9.7% identity, respectively, and four other TRIM genes, TRIM73, TRIM55, TRIM10, and TRIM43, had highly significant identities, greater than 5% (Table 2).

When human INF genes were compared with Ag36 (GenBank M21331), IFN-α was 13.6% identical, IFN-β was 12.6% identical, and IFN-γ was 17.9% identical. Studies by Cunha-Neto et al (19), and , Marin-Neto et al (20) suggest that IFN-γ signaling in the myocardium is associated with human CCC as well as with membrane cofactor protein-1, which is increased with the expression of atrial natriuretic factors. These both are markers of cardiomyocyte hypertrophy and heart failure in neonatal murine cardiomyocytes. These findings suggest that IFN- γ mediated chronic myocardial inflammation could contribute to the pathogenesis of CCC. In addition, the cytokine profile associated with Chagas’ myocarditis is shifted toward Th1 cytokines, with elevated INF- γ levels, and decreased IL-10 levels which may theoretically prolong an ongoing inflammatory process (17; 21; 22). Recent studies of a useful mouse model of CCC by (31; 32) revealed the additional roles of fibrosis and residual parasites and the associated signaling pathways in CCC.

The 37 T. cruzi MAP genes’ partial identities to those human immune genes, which are conserved over the hundreds of millions of years separating Protozoa and Humans, may be relevant to the parasite’s resistance to the mammalian innate immune system during infection. For example, RNA interference from the MAP gene mRNA could decrease the expression of these genes. Experiments to test this hypothesis would measure host IFN-α, IFN-β, and IFN-γ and the four relevant TRIM proteins during infection compared with non-infected cells.

ACKNOWLEDGEMENTS

The authors would like to thank Abbott Laboratories and our colleagues where the foundational investigations were performed. The Galaxy server that was used for some calculations is in part funded by Collaborative Research Centre 992 Medical Epigenetics (DFG grant SFB 992/1 2012) and German Federal Ministry of Education and Research (BMBF grants 031 A538A/A538C RBC, 031L0101B/031L0101C de.NBI-epi, 031L0106 de.STAIR (de.NBI)).

AUTHOR CONTRIBUTIONS

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Drs. Martin A. Winkler and Alfred A. Pan. All authors read and approved the final manuscript.

COMPETING INTERESTS

The authors have no relevant financial or non-financial interests to disclose. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

DATA AVAILABILITY STATEMENT

The datasets generated during and/or analyzed during the current study are available in the online Galaxy repositories:

https://usegalaxy.eu/u/martinawinklerphd/h/copy-of-copy-of-mammalian-trim-genes-compared-with-antigen-36 and

https://usegalaxy.org/u/martinawinklerphd/h/ag36-and-mammalian-trim21-homologies.

Above URLs last accessed 05/16/2021.

These bioinformatics workflows are available to all, but registration (which is free) is required to view the results.

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Species’ Genbank accession numbers at http://www.ncbi.nlm.nih.gov

Homo sapiens TRIM21 M34551

Trypanosoma cruzi Clone 36 Antigen M21331

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No competing interests reported.

Tables 1-4 are available in the supplementary files section.

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Molecular Similarities Between Trypanosoma Cruzi Microtubule Associated Proteins, Mammalian Interferons, and TRIM Genes

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